THE DISSERTATION GENERAL CHARACTERISTIC

Work urgency

Mucoviscidosis (MV) – the most frequent autosomno-retsessivnoe the disease caused by a mutation of gene CFTR (cystic fibrosis transmembrane conductance regulator), characterised by clinical polymorphism [Kapranov N.I.

Considering objective complexities of carrying out of etiotropic treatment, the researches specifying pathogenetic mechanisms of disease that allows to develop new directions of therapy MV [Kapranov N.I., Kashirskaja N.J., etc., 2009] all over the world are activly carried out. Despite steadfast attention of researchers to questions of a pathogenesis of disease, there are obscure mechanisms genetic, immune and immunoreguljatornyh the disturbances promoting advance of an illness at children, especially taking into account character of a chronic respiratory infection since the individual ensemble of factors virulentnosti microbic agents in many respects defines features of the immunologic answer and the further current of disease.

The most actual, for today, studying immunoreguljatornyh relations is at sepatsionnoj infections which can lead to formation of serious, uncontrollable pyoinflammatory process in a respiratory tract and  destruction of patient MV within 2th years after a becoming infected [to Kapranov N.I., Kashirskaja N.J., etc., 2009, Semykin S.J., 2009, Amelina E.L., 2008].

Considering an immune genesis of a multiorgan lesion at MV, the further prospects of studying are bound to transfer of researches into molekuljarno-genetic level, search of direct precursors of fibers of the cascade of a complement, tsitokinovyh molecules and their receptors on different levels of development of the congenital and got immunity.

Proceeding from stated, carrying out of complex research of genes-modifiers of the immune answer, indicators of congenital immunity and tsitokinovoj is represented actual to regulation taking into account a clinical picture and character of microbic colonisation at patients MV that will allow to prognosticate the further current of disease, and will promote creation new immunokorregirujushchih rehabilitational programs for the given category of patients.

The work purpose: to Develop new diagnostic and prognostic criteria of a current of a mucoviscidosis at children on the basis of the multicomponent analysis genetic, microbiological, immunoreguljatornyh and nonspecific factors.

Research problems

1. To specify frequency of occurrence of a mucoviscidosis in the Astrakhan area according to neonatal screening.

2. To define clinico-anamnesticheskie features of a current of disease and to analyse frequency of virus and is bacteriemic-inflammatory diseases vnelegochnoj localisations at sick of a mucoviscidosis, depending on gravity of a current of disease and character of microbic colonisation in a bronchial tree.

3. To study a condition of factors of congenital immunity (lysozyme level in a sputum and blood serum, bactericidal activity of blood serum, komplementarnogo the status) sick of a mucoviscidosis depending on gravity, a phase of disease and the microbiological respiratory status.

4. To establish clinico-pathogenetic and diagnostic value of leaders about - (SILT-1 β, ИЛ-6, ИЛ-8, IFN - α, IFN - γ) and antiinflammatory (ИЛ-4, ИЛ-10) cytokines in blood serum and a sputum at sick of a mucoviscidosis taking into account character of a respiratory infection and gravity of a current of disease.

5. On the basis of the received data about a condition of factors of congenital immunity and reguljatornyh cytokines to develop the prognostic criteria defining a variant of the further current of disease after becoming infected Burkholderia cepacia.

6. To analyse frequencies of polymorphisms in genes IFN - γ, ИЛ-4, Rа ИЛ-4 among sick of a mucoviscidosis and healthy individuals.

7. To study associations of polymorphisms in the specified genes with a current bronholegochnogo process and with character of a lesion of system of digestion at sick of a mucoviscidosis.

Scientific novelty of work

For the first time the complex analysis of data microbiological, genetic and clinico-immunologicheskogo inspections at sick of a mucoviscidosis is carried out.

For the first time frequency of occurrence of a mucoviscidosis according to neonatal screening in Astrakhan and the Astrakhan area is defined.

At patients MV essential differences of factors of congenital immunity and tsitokinovoj regulations, assotsiirovannye with character of microbic colonisation of a bronchial tree for the first time are taped. The important role of disturbance immunoreguljatornyh mechanisms (tsitokinovogo a link, indicators of congenital immunity) in advance bronholegochnogo process at patients MV is confirmed. New additional differentsialno-diagnostic criteria of a phase bronholegochnogo process at patients MV are established.

For the first time authentic differences in indicators tsitokinovoj regulations at patients with fulminantnym and a stable current of disease after colonisation of bronchial tree B are taped. сepacia. On the basis of the spent profound statistical analysis clinico-anamnesticheskih and datas of laboratory the prognostic factors defining the further current of disease after infection Burkholderia cepacia for the first time are taped.

For the first time the estimation of frequencies of alleles and genotypes of polymorphic locuses of genes IFN γ, ИЛ-4, ИЛ-4Rа in sample of patients MV living in territory of the Russian Federation is received. The analysis of communications of the given polymorphic locuses with clinical implications of a mucoviscidosis is carried out and associations with gravity bronholegochnoj pathologies and some complications MV, such as a cirrhosis and chronic pulmonary heart are taped. For the first time at patients MV the association of genotypes T/S and S/S polymorphism Т-1488С of a gene IFN - γ c by more favorable development bronholegochnogo process and features of a lesion of a gastroenteric tract is taped.

For the first time the gravity association bronholegochnogo process at patients MV with mutant allelem C is shown updating 3 ’-UTR G/C gene ИЛ-4.

For the first time the association allelja I gene ИЛ-4Ra with more serious current bronholegochnogo process and formation of chronic pulmonary heart at patients MV is taped.

For the first time it is established, that polymorphisms Т-1488С of a gene IFN - γ and 3 ’-UTR G/C gene ИЛ-4 are functionally significant and influence expression levels kodiruemyhtsitokinov.

The practical importance

Results of work have essential value for applied medicine as open the important pathogenetic mechanisms of a mucoviscidosis at children taking into account features of a chronic respiratory infection.

Definition of prevalence of a mucoviscidosis in region allows to improve organizational and methodical actions for rendering of the mediko-social help to the given contingent of patients.

Interpreting of immunologic indicators, with the account clinico-anamnesticheskih, microbiological and datas of laboratory allows to dilate essentially therapy possibilities, to define strategy immunomodulirujushchih influences, in particular interferonsoderzhashchimi preparations and lysozyme preparations that will promote reduction of number of relapses and an induction of long remission. The important practical value of definition of levels ИЛ-6, ИЛ-8, С5а, a lysozyme in blood serum, the BASQUE as additional differentsialno-diagnostic criteria of a phase bronholegochnogo process and an estimation of efficiency of spent therapy at patients with a mucoviscidosis is established.

The taped features tsitokinovoj regulations at patients MV, at various types of clinical reactions, assotsiirovannyh with colonisation B. сepacia, allow to prognosticate the further current of disease, to spend correction of therapy and to provide territorially separation of patients.

Results of work bring the contribution to the general representation about genes-modifiers of clinical picture MV. The taped associations of genetic polymorphisms IFN - γ (Т-1488С), ИЛ-4 (3 ’-UTR G/C) and ИЛ-4Rа (I50V) with gravity bronholegochnoj and a number of complications (a cirrhosis, chronic pulmonary heart) at patients MV allow to recommend to a pathology genotipirovanie patients MV for presence of adverse alleles of these genes for obektivizatsii the forecast of a current of disease and development of more rational tactics of treatment.

The positions which are taken out on protection

1. Gravity of a mucoviscidosis and the disease forecast are defined by a variant of a genetic mutation and character of infectious process, assotsiiruemogo with a kind of the microbic agent in a bronchial tree. Chronic colonisation of a respiratory tract by a Gram-negative microflora causes high frequency of development both an accompanying pathology, and complications vnelegochnoj and pulmonary localisation. The in the lead position in development of complications, belongs B.cepacia.

2. At patients MV it is observed expressed disbalans factors of congenital immunity: in process of advance bronholegochnogo process intensifying of rates of activation in complement system, activity depression muramidazy, change of activity the BASQUE and as rising of synthesis proinflammatory and protivospalitelnyh cytokines as in blood serum, and is immediate in the lesion centre – a respiratory tract is defined.

3. Degree and expression disbalansa factors of congenital immunity depends on character of the dominating infectious agent in a bronchial tree. tsitokinovyj the cascade at children sick MV, at colonisation by Gram-negative flora, reflects excessive activation monotsitarno-makrofagalnogo an immunity link (rising of caption ИЛ-1 β, ИЛ-6, ИЛ-8) and T-helperov 2 types (increase ИЛ-4, ИЛ-6) against depression reguljatornoj the importance IFN - γ. At inflammatory process, assotsiirovannom with a staphylococcal infection, more adequate immune answer with moderate activity tsitokinovogo a profile that provides safety of morphological structures of lungs and high indicators FVD is observed. At patients, with colonisation of respiratory tract B. cepacia, at fulminantnom a disease current, in biological liquids it is sharply expressed disbalans tsitokinovoj to regulation in comparison with patients with a stable clinical current that can be used for forecasting of the further current of disease.

4. Differences in intensity tsitokinovogo the answer are caused on the one hand by features of a chronic respiratory infection, with another – influence of genes, as CFTR, and genes-modifiers of the immune answer. The gravity association bronholegochnogo process is established at MV with polymorphism 3 ’-UTR G/C gene ИЛ-4 and mutation I50V of gene ИЛ-4Ra. At patients MV having mutant alleles ИЛ-4 and ИЛ-4Ra, more serious implications from the party bronholegochnoj systems are noted. Patients with mutant allelem polymorphism Т-1488С IFN - γ are characterised by safe function of lungs at the senior school age and more favorable microbiological landscape of a sputum (low level of colonisation of a Gram-negative microflora). The association of implications from a gastroenteric tract at patients MV, with gene polymorphisms IFN - γ is taped. The early manifestation of an intestinal syndrome and augmentation of frequency of a cirrhosis among patients, carriers mutant allelja With on polymorphism Т-1488С IFN - γ is established.

Work approbation

Dissertation substantive provisions are reported at scientifically-practical conferences of employees AGMA and doctors of the Astrakhan area on medicine pressing questions (Astrakhan, 2007, 2008, 2009, 2010г.г.), Astrakhan regional scientifically-practical conference «the Medicine and health of the person» (Astrakhan 2006, 2007, 2008, 2009г.г.), sessions of the Astrakhan unit of the Union of Pediatrists of Russia; XV, XVI, XVII Russian National Congresses «the Person and a medicine» (Moscow, 2007, 2009, 2010г.г.), the All-Russia Congress «New technologies in pediatrics and children's surgery» (Moscow, 2007г.) VIII and IХ, H the National Congress on a mucoviscidosis (Yaroslavl, 2008г., Moscow, 2009г. Yaroslavl, 2011), the congresses of pediatrists of Russia (Moscow 2005, 2010г, 2011) at Republican scientifically-practical conference «New technologies in diagnostics and treatment of illnesses of organs of breath at children and teenagers» (Almaty, 2009), on ХIV, ХV the international congresses on aftertreatment and immunoreabilitatsii (Dubai, 2009г., Tel Aviv, 2010г.).

Introduction in practice

Materials of researches are introduced in work pulmonologicheskogo units of MUSES of II City children's hospital, GUZ ODKB of N.N.Silishchevoj by of Astrakhan, MUSES of VII City children's hospital of of Volgograd. The data obtained as a result of research are included in a lecture material, used on a practical training with students, interns, clinical interns and cadets of faculty of postdegree formation of the Astrakhan state medical academy, included in methodical references and managements for doctors.

Publications

On dissertation materials 50 works are published, with that number 12 in the reviewed magazines recommended VAK the Russian Federation, 1 monography, 1 uchebno-methodical grant is let out, the demand for the invention (№2010150417 (072777) the priority inquiry from 08.12.2010г is submitted.).

Volume and dissertation structure

The dissertation is stated on 296 pages of the typewritten text. Work includes following sections: introduction, the literary review, materials and research methods, 7 heads of own observations, discussion of the received data, conclusions, practical references. The literature list includes 312 sources, from them 101 domestic and 211 foreign. Work is illustrated by 54 tables and 29 drawings.